Chemopreventive Efficacy and Mechanism of Licofelone in a Mouse Lung Tumor Model via Aspiration

Abstract

Our previous study comparing inhalation and aspiration to administer agents directly to lung indicated that aspiration route is as effective as inhalation while reducing costs for equipment and chemopreventive agent. This study evaluated the chemopreventive efficacy and mechanism of Licofelone, a dual inhibitor of cyclooxygenase-2 (Cox-2) and 5-lipoxygenase (5-Lox), via oropharyngeal aspiration against mouse lung adenoma. Eight week old female A/J mice were given three doses of benzo[a]pyrene (B[a]P, 2 mg/dose, gavage) to induce lung adenomas. After dysplasia developed, the mice were given Licofelone (0, 0.03, 0.1 or 0.3 mg/kg) for 16 weeks and tumor incidence and multiplicity in lung were measured. In addition, the expression of a series of biomarkers in lung cancer progression was evaluated at 2 and 16 weeks. Licofelone showed dose-related inhibition of B[a]P-induced tumor incidence and multiplicity at 0.03 and 0.1 mg/kg following 16-week treatment. Licofelone also showed dose-dependent inhibition of Cox-2 (25–41%) and 5-Lox (35–61%) at 2 and 16 weeks and proliferating cell nuclear antigen (PCNA, 41–61%) at 16 weeks. A dose-dependent increase in apoptosis (1.5–2.4-fold) was also observed in Licofelone groups. A marginal inhibition of survivin was observed at one dose. In conclusion, this study demonstrated that Licofelone via aspiration showed chemopreventive efficacy against mouse lung adenoma with good correlation to early and late biomarkers of lung cancer progression. This is the first study to show that the aspiration route can be an excellent inexpensive alternative to inhalation for direct delivery of drugs to rodent lungs for efficacy testing of potential chemopreventive agents.

Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX–LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice

“…A dose-dependent inhibition of PCNA expression with an increase in apoptosis also was observed in licofelone-treated lung tumors (16) as well as colon tumors (15, 37). Similarly, dose-dependent inhibition of COX-2 and 5-LOX was observed with licofelone treatment in lung tumors (16). We found that licofelone had a modulatory effect on cell-cycle regulatory proteins like Cyclin E and p16.…”

“…Licofelone inhibited colonic tumors in a mouse colon cancer model by 72-100%, caused a significant reduction in small intestinal polyps (15), and provided better efficacy that did celecoxib in suppressing tumor growth. In a benzo( a )pyrene-induced lung cancer model, licofelone inhibited tumor multiplicity by 26% with a significant decrease in tumor incidence (16). …”

“…Licofelone is one such compound that is currently in phase III clinical trials for treatment of pain and inflammation associated with osteoarthritis (12, 13) and also has been shown to prevent colon (14, 15), lung (16) and prostate cancers (17). However no studies have been reported on the chemopreventive effects of licofelone in urothelial cancer.…”

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

“…Mice were infected with adeno-Cre and transferred to a tamoxifen-containing diet, as in the earlier experiments. Two weeks following the addition of tamoxifen, mice were treated with either vehicle or licofelone-a dual COX/5-LOX pathway inhibitor, which has shown promising chemopreventive efficacy in lung and colon cancers (34,35). Remarkably, after only four doses we found substantially reduced tumor load when compared with vehicletreated controls (Fig.…”

Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone

“…To date, several NSAIDs with dual COX-2/5-LO activity have undergone clinical testing for use in the treatment of inflammatory diseases, with licofelone (2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetic acid) being the most advanced. In addition to demonstrating an excellent tolerability, licofelone has been shown to have a dose-dependent anticancer effect in cell culture and in animal models (20–22). So far studies have focused on the ability of licofelone to directly inhibit PG (21) and LT synthesis (23) and induce apoptosis in tumor cells; however, little is known about its direct effects on immune cell populations in the context of cancer.…”